1-(2'-Deoxy-2',2'-difluoro-D-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride (also known as 2'-deoxy-2',2'-difluorocytidine hydrochloride or gemcitabine hydrochloride - see Formula I) is one of a series of 2'-deoxy-2',2'-difluoronucleosides known in the art. For example, such compounds are disclosed and taught to have antiviral activity in U.S. Pat. Nos. 4,526,988 and 4,808,614. European Patent Application Publication 184,365 teaches that these same difluoronucleoside agents have oncolytic activity. In fact, gemcitabine hydrochloride is undergoing clinical evaluation to determine its usefulness as a treatment for a variety of cancers, such as pancreatic cancer. ##STR1##
The synthesis of gemcitabine is a multi-step process--see U.S. Pat. Nos. 4,526,988, 4,808,614, and 5,223,608 and European Patent Application Publications 577,303, 577,304, and 587,364. Most of these synthetic routes go through the penultimate intermediate .beta.-1-(2'-deoxy-2',2'-difluoro-3',5'-di-O-benzoyl-D-ribofuranosyl)-4-am inopyrimidin-2-one which is deprotected and salified to give the final desired product as the hydrochloride salt. For example, in U.S. Pat. No. 5,223,608, at column 10, line 41 et seq., it is taught that the benzoyl protecting groups "are removed by hydrolysis with a strong or moderately strong base". It is also taught that "[a]t least one mole equivalent of base is needed for each protecting group." Examples 7 and 11 of this patent teach the use of anhydrous ammonia in methanol for accomplishing this deprotection which results in the formation of ammonium chloride which is insoluble in the organic solvents used and must be removed by treatment with water.
The preparation of gemcitabine hydrochloride salt is also disclosed in the literature. U.S. Pat. No. 5,223,608, at column 11, line 22 et seq., and Example 8 where hot isopropanol and concentrated hydrochloric acid are used to generate the crystalline gemcitabine hydrochloride.
This invention provides a more economical and higher yielding process for preparing gemcitabine hydrochloride which avoids the use of excess base and loss of product due to the presence of water.